Guidance for Industry

Non-Penicillin Beta-Lactam
Risk Assessment:
A CGMP Framework
DRAFT GUIDANCE
This guidance document is being distributed for comment purposes only.
Comments and suggestions regarding this draft document should be submitted within 60 days of
publication in the Federal Register of the notice announcing the availability of the draft
guidance. Submit comments to the Division of Dockets Management (HFA-305), Food and
Drug Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852. All comments
should be identified with the docket number listed in the notice of availability that publishes in
theFederal Register.
For questions regarding this draft document contact (CDER) Edwin Melendez 301-796-3284.
U.S. Department of Health and Human Services
Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
March 2011
Current Good Manufacturing Practices (CGMPs)





























Guidance for Industry
Non-Penicillin Beta-Lactam
Risk Assessment:
A CGMP Framework
Additional copies are available from:
Office of Communications
Division of Drug Information, WO51, Room 2201
Center for Drug Evaluation and Research
Food and Drug Administration
10903 New Hampshire Ave.
Silver Spring, MD 20993-0002
Phone: 301-796-3400; Fax: 301-847-8714
druginfo@fda.hhs.gov
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm
U.S. Department of Health and Human Services
Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
March 2011
Current Good Manufacturing Practices (CGMP)







































Contains Nonbinding Recommendations
Draft Not for Implementation
TABLE OF CONTENTS
I. INTRODUCTION....................................................................................................................1
II. BACKGROUND ......................................................................................................................2
III. RECOMMENDATIONS.........................................................................................................6
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Contains Nonbinding Recommendations
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1 Guidance for Industry
1
2
3 Non-Penicillin Beta-Lactam Risk Assessment:
4 A CGMP Framework
5
6
7
8 This draft guidance, when finalized, will represent the Food and Drug Administration's (FDA's) current
9 thinking on this topic. It does not create or confer any rights for or on any person and does not operate to
10 bind FDA or the public. You can use an alternative approach if the approach satisfies the requirements of
11 the applicable statutes and regulations. If you want to discuss an alternative approach, contact the FDA
12 staff responsible for implementing this guidance. If you cannot identify the appropriate FDA staff, call
13 the appropriate number listed on the title page of this guidance.
14
15
16
17 I. INTRODUCTION
18
19 This guidance describes the importance of implementing appropriate steps during the
20 manufacturing process to prevent cross-contamination of finished pharmaceuticals and active
21 pharmaceutical ingredients (APIs) with non-penicillin beta-lactam antibiotics. This guidance
22 also provides information regarding the relative health risk of, and the potential for, cross-
23 reactivity in the classes of sensitizing beta-lactams (penicillins and non-penicillin beta-lactams).
24 This guidance is intended to assist manufacturers in assessing whether separate facilities should
25 be used based on the relative health risk of cross-reactivity.
26
27 Drug cross-contamination is the contamination of one drug with one or more different drugs.
28 Penicillin can be a sensitizing agent that triggers a hypersensitive exaggerated allergic immune
29 response in some people. Accordingly, developing strategies to prevent cross-contamination of
30 other drugs with penicillin is a key element of manufacturing penicillin. Non-penicillin beta-
31 lactam drugs may also be sensitizing agents, and cross-contamination with non-penicillin beta-
32 lactam drugs can initiate drug-induced hypersensitivity reactions, including anaphylaxis, an
33 allergic reaction that may be a life-threatening event. As with penicillin, a critical aspect of
34 manufacturing non-penicillin beta-lactam drugs is preventing cross-contamination to reduce the
35 potential for drug-induced, life-threatening allergic reactions.
36
37 The information in this guidance is intended for manufacturers of finished pharmaceuticals and
38 APIs, including repackagers. Other establishments that handle drugs, such as pharmacy
39 compounders, may find this information useful.
40
1
This guidance was developed by the Office of Compliance, Division of Manufacturing and Product Quality, in the
Center for Drug Evaluation and Research (CDER) at the Food and Drug Administration.
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Contains Nonbinding Recommendations
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41 FDA's guidance documents, including this guidance, do not establish legally enforceable
42 responsibilities. Instead, guidance documents describe the Agencys current thinking on a topic
43 and should be viewed only as recommendations, unless specific regulatory or statutory
44 requirements are cited. The use of the word should in FDA guidance means that something is
45 suggested or recommended, but not required.
46
47 II. BACKGROUND
48
49 Section 501(a)(2)(B) of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 351(a)(2)(B))
50 requires that, with few exceptions, all drugs be manufactured in compliance with current good
51 manufacturing practices (CGMPs). Drugs that are not in compliance with CGMPs are
52 considered to be adulterated. Furthermore, finished pharmaceuticals are required to comply with
53 the CGMP regulations at 21 CFR parts 210 and 211.
54
55 Several CGMP regulations directly address facility and equipment controls and cleaning. For
56 example, 211.42(c) requires building and facility controls in general to prevent cross-
57 contamination of drug products. Specifically, the regulation states, [t]here shall be separate or
58 defined areas or such other control systems for the firms operations as are necessary to prevent
59 contamination or mix-ups during manufacturing, processing, packaging, storage, and holding
60 processes.
61
62 With respect to penicillin, 211.42(d) requires that [o]perations relating to the manufacture,
63 processing, and packing of penicillin shall be performed in facilities separate from those used for
64 other drug products for human use. However, FDA has clarified that separate buildings may
65 not be necessary, provided that the section of the manufacturing facility dedicated to
66 manufacturing penicillin is structurally isolated (i.e., completely and comprehensively separated)
67 from the areas of the facility in which non-penicillin products are manufactured.
2
Under
68 211.46(d), manufacturers must completely separate air handling systems for penicillin from
69 those used for other drugs for human use. Similarly, 211.176 requires manufacturers to test
70 non-penicillin drug products for penicillin where the possibility of exposure to cross-
71 contamination exists, and prohibits manufacturers from marketing such products if detectable
72 levels of penicillin are found.
3
73
74 Although FDA has not issued CGMP regulations specific to APIs, the Agency has provided
75 guidance to API manufacturers in the guidance for industry, ICH
4
Q7, Good Manufacturing
2
Preamble to the final rule, Current Good Manufacturing Practice, Processing, Packing, or Holding, published in
the FEDERAL REGISTER of September 29, 1978 (43 FR 45014 at 45038).
3
See A Review of Procedures for the Detection of Residual Penicillins in Drugs (Appendix I, Procedures for
Detecting and Measuring Penicillin Contamination in Drugs, FDA By-Lines No. 8 (November 1977)), available at
http://www.fda.gov/downloads/AboutFDA/CentersOffices/CDER/UCM095812.pdf.
4
International Conference on Harmonization.
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Contains Nonbinding Recommendations
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76 Practice Guidance for Active Pharmaceutical Ingredients (ICH Q7 guidance).
5
Because some
77 APIs are sensitizing compounds that may cause anaphylactic shock, preventing cross-
78 contamination in APIs is as important as preventing cross-contamination in finished products.
79 The ICH Q7 guidance recommends using dedicated production areas, which can include
80 facilities, air handling equipment, and/or processing equipment, in the production of highly
81 sensitizing materials, such as penicillins and cephalosporins.
6
82
83 Beta-lactam antibiotics share a basic chemical structure that includes a three-carbon, one-
84 nitrogen cyclic amine structure known as the beta-lactam ring. The side chain associated with the
85 beta-lactam ring is a variable group attached to the core structure by a peptide bond. The side
86 chain variability contributes to antibacterial activity.
87
88 As of the date of this publication, FDA has approved over 34 beta-lactam compounds as active
89 ingredients in drugs for human use.
7
Beta-lactam antibiotics include the following five classes:
90
91 penicillins (e.g., ampicillin, oxacillin)
92 cephalosporins (e.g., cephalexin, cefaclor)
93 penems (e.g., imipenem, meropenem)
94 carbacephems (e.g., loracarbef)
95 monobactams (e.g., aztreonam)
8
96
97 The penicillins, cephalosporins, penems, and carbacephems share a characteristic bicyclic core
98 structure, which is believed to initiate allergic reactions. The monobactam aztreonam has a
99 unique monocyclic beta-lactam nucleus and rarely cross-reacts with penicillins and
100 cephalosporins.
9
Aztreonam and ceftazidime have a common side chain, and cross-reactivity
101 between aztreonam and ceftazidime has been reported.
10
102
5
We update guidance documents periodically. To make sure you have the most recent version of a guidance, check
the Guidance Page at
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm.
6
See section IV.D Containment (4.4) of the ICH Q7 guidance.
7
Approved beta-lactam antibiotics are listed in FDAs Approved Drug Products with Therapeutic Equivalence
Evaluations, generally known as the Orange Book (available on the Internet at
http://www.accessdata.fda.gov/scripts/cder/ob/default.cfm). The Orange Book is searchable by active ingredient
and updated as newer drug products are added.
8
Yao, J DC, and RC Moellering, J r., Antibacterial agents, in Manual of Clinical Microbiology, 9
th
edition, edited by
PR Murray et al., Washington D.C., ASM Press, 2007.
9
American Academy of Allergy, Asthma, and Immunology, 1999, Disease management of drug hypersensitivity: a
practice parameter, Ann Allergy Asthma Immunol, 83(supp): S665-S700.
10
Perez Pimiento, A, M Gomez Martinez, A Minguez Mena, A Trampal Gonzalez, S de Paz Arranz, and M
Rodriguez Mosquera, 1998, Aztreonam and ceftazidime: evidence of in vivo cross-allergenicity, Allergy, 53:624-
625.
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103 Beta-lactam antibiotics inhibit bacterial cell wall synthesis. Many bacteria produce beta-
104 lactamases, which are enzymes that degrade and inactivate beta-lactam antibiotics. Beta-lactam
105 compounds such as clavulanic acid, tazobactam, and sulbactam have weak antibacterial activity
106 but are irreversible inhibitors of many beta-lactamases; they are used in combination with
107 specific beta-lactam agents to preserve antibacterial activity.
108
109 Allergic reactions associated with penicillins and non-penicillin beta-lactam antibiotics range
110 from rashes to life-threatening anaphylaxis. Immunoglobulin E (IgE) antibodies mediate the
111 immediate hypersensitivity reactions that are responsible for the symptoms of hay fever, asthma,
112 hives, and anaphylactic shock. IgE-mediated hypersensitivity reactions are of primary concern
113 because they may be associated with significant morbidity and mortality. There is evidence that
114 patients with a history of hypersensitivity to penicillin may also experience IgE-mediated
115 reactions to cephalosporins and penems.
11
Cross-reactivity (cross-sensitivity) between beta-
116 lactam products has been and continues to be a major concern in the manufacture of drugs.
117
118 All non-penicillin beta-lactam antibiotics also have the potential to sensitize individuals, and
119 subsequent exposure to penicillin may result in severe allergic reactions in some patients.
120 Although the frequency of hypersensitivity reactions due to cross-reactivity between beta-lactam
121 classes can be lower than the risk within a class,
12
the hazard posed is present
13
and potentially
122 life-threatening. The potential health hazard of non-penicillin beta-lactam drugs is therefore
123 similar to that of penicillins. Further similarities between non-penicillin beta-lactam antibiotics
124 and penicillins are as follows:
125
126 It is difficult to define the minimal dose below which allergic responses are unlikely to
127 occur in humans.
14
128 There is a lack of suitable animal or receptor testing models that are predictive of human
129 sensitivity.
15
130 The threshold dose at which allergenic response could occur is extremely low and
11
Saxon, A, DC Adelman, A Patel, R Hajdu, and GB Calandra, 1988, Imipenem cross-reactivity with penicillin in
humans, J Allergy Clin Immunol, 82:213-217; Saxon, A, GN Beall, AS Rohr, and DC Adelman, 1987, Immediate
hypersensitivity reactions to beta-lactam antibiotics, Ann Intern Med, 107(2):204-215; Prescott, J r., WA, DD
DePestel, JJ Ellis, and RE Regal, 2004, Incidence of carbapenem-associated allergic-type reactions among patients
with versus patients without a reported penicillin allergy, Clin Infect Dis, 38:1102-1107.
12
Salkind, AR, PG Cuddy, and J W Foxworth, 2001, Is this patient allergic to penicillin? An evidence-based analysis
of the likelihood of penicillin allergy, J AMA, 285:2498-2505.
13
Khan, D. and R Solensky , 2010, Drug Allergy, J Allergy Clin Immunol. 125(2): S131.
14
Dayan, AD, 1993, Allergy to antimicrobial residues in food: assessment of the risk to man, Vet Microbiol,
35:213-226; Blanca, M, J Garcia, J M Vega, A Miranda, MJ Carmona et al., 1996, Anaphylaxis to penicillins after
non-therapeutic exposure: an immunological investigation, Clin Exp Allergy, 26:335-340.
15
Olson, H, G Betton, D Robinson, K Thomas, A Monro et al., 2000, Concordance of the toxicity of
pharmaceuticals in humans and in animals, Regul Toxicol Pharmacol, 32:56-67.
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131 difficult to detect with current analytical methods.
16
132
133 Some beta-lactam intermediate compounds and derivatives possess sensitization and cross
134 reactivity properties. Beta-lactam chemical manufacturing processes including, but not limited
135 to, fermentation and synthesis may create beta-lactam intermediates or derivatives with unknown
136 health consequences. Therefore, the health risk of sensitization and cross-reaction is difficult to
137 predetermine for beta-lactam intermediates, and is not always well-defined.
138
139 Beta-lactam intermediate compounds are usually API precursor materials that undergo molecular
140 change or purification before use in the manufacture of beta-lactam antibiotic APIs. As a result
141 of these changes, the intermediate compounds may develop antigenic characteristics that can
142 produce allergic reactions. For example, 6-aminopenicillanic acid (6-APA) serves as the
143 intermediate for the formation of all synthetic penicillins that are formed by attaching various
144 side chains. The structure of 6-APA includes unbroken beta-lactam and thiazolidine rings. The
145 beta-lactam ring is relatively unstable, and it commonly breaks open. In the case of 6-APA, this
146 breakage leads to the formation of a penicilloyl moiety, which is also known as the major
147 antigenic determinant of penicillin. This moiety is thought to be a common cause of penicillin
148 urticarial reaction.
17
Degradation of 6-APA can also result in the formation of minor antigenic
149 determinants, including penicilloic acids, penaldic acid, and penicillamine. Anaphylactic
150 reactions to penicillins are usually due to IgE antibodies to minor determinants. Therefore,
151 although 6-APA is not a true antibiotic, it still carries with it a potential to induce allergenicity.
152
153 Derivatives are unintended by-products that occur during the manufacturing process (i.e., an
154 impurity or degradant) which could have sensitizing properties. Similar to intermediates, beta-
155 lactam derivatives may also develop antigenic properties that can produce allergic reactions.
156
157 Beta-lactam antibiotics are similar to one another in many ways, but they may differ in
158 pharmacokinetics, antibacterial activity, and potential to cause serious allergic reactions.
159 Because allergy testing methods have not been well-validated,
18
it is clinically difficult to
160 determine the occurrence and rate of cross-reactivity between beta-lactam antibiotics in humans.
161 Therefore, undiagnosed or underreported cases of cross-reactivity likely exist. Some beta-lactam
162 antibiotics have negligible potential for cross-reactivity with beta-lactams of other classes,
163 whereas other beta-lactam compounds may exhibit sensitizing activity as derivatives before the
164 incorporation of side chains that confer antibacterial activity.
165
16
Perez Pimiento, A, M Gomez Martinez, A Minguez Mena, A Trampal Gonzalez, S de Paz Arranz, and M
Rodriguez Mosquera, 1998, Aztreonam and ceftazidime: evidence of in vivo cross-allergenicity, Allergy, 53:624-
625; Shepard, GM, 1991, Allergy to B-lactam antibiotics, Immunol Allergy Clin North Am, 11(3):611-633.
17
Middleton Principle of Allergy and Immunology: Principles and Practice, 2009 edition, chapter 68: Drug Allergy,
electronic book version, at the sentence above Figure 68.2.
18
Bernstein, IL, J T Li, DI Bernstein, et al., 2008, Allergy diagnostic testing: an updated practice parameter, Ann
Allergy Asthma Immunol, 100:S1-S148.
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166 III. RECOMMENDATIONS
167
168 Because of the health risks associated with cross-reactivity (cross-sensitivity) of beta-lactams,
169 non-beta-lactam manufacturers should assess and establish stringent controls (including
170 appropriate facility design provisions assuring separation) to prevent cross-contamination. J ust
171 as FDA considers the separation of production facilities for penicillins to be current good
172 manufacturing practice, FDA expects manufacturers to treat sensitizing non-penicillin beta-
173 lactam-based products similarly. Specifically, FDA recommends that manufacturers establish
174 appropriate separation and control systems designed to prevent the following types of cross-
175 contamination:
176
177 Non-penicillin beta-lactam contamination in a non-beta-lactam product (e.g., cefaclor in
178 aspirin)
179 Non-penicillin beta-lactam contamination in another non-penicillin beta-lactam (e.g.,
180 cephalexin in imipenem)
181
182 As with penicillin, the section of a facility dedicated to manufacturing a sensitizing non-
183 penicillin beta-lactam should be structurally isolated (i.e., completely and comprehensively
184 separated) from areas in the facility in which other products are manufactured. This control
185 applies to each of the five classes of sensitizing beta-lactams; the area in which any class of
186 sensitizing beta-lactam is manufactured should be separated from areas in which any other
187 products are manufactured, including any other class of sensitizing beta-lactam or any other non-
188 beta-lactam product. Manufacturing that is restricted to a specific class of beta-lactam
189 compound (e.g., the cephalosporin family of products) would generally not mandate separate
190 facilities and air handling systems, and could permit production campaigning and cleaning as
191 sufficient control.
6